Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

Autores
Davis, Hannah M.; Pacheco Costa, Rafael; Atkinson, Emily G.; Brun, Lucas Ricardo Martín; Gortazar, Arancha R.; Harris, Julia; Hiasa, Masahiro; Bolarinwa, Surajudeen A.; Yoneda, Toshiyuki; Ivan, Mircea; Bruzzaniti, Angela; Bellido, Teresita; Plotkin, Lilian I.
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
Fil: Davis, Hannah M.. Indiana University; Estados Unidos
Fil: Pacheco Costa, Rafael. Indiana University; Estados Unidos
Fil: Atkinson, Emily G.. Indiana University; Estados Unidos
Fil: Brun, Lucas Ricardo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Indiana University; Estados Unidos
Fil: Gortazar, Arancha R.. Universidad San Pablo; España
Fil: Harris, Julia. Indiana University; Estados Unidos
Fil: Hiasa, Masahiro. Indiana University; Estados Unidos
Fil: Bolarinwa, Surajudeen A.. Indiana University; Estados Unidos
Fil: Yoneda, Toshiyuki. Indiana University; Estados Unidos
Fil: Ivan, Mircea. Indiana University; Estados Unidos
Fil: Bruzzaniti, Angela. Indiana University; Estados Unidos
Fil: Bellido, Teresita. Indiana University; Estados Unidos
Fil: Plotkin, Lilian I.. Indiana University; Estados Unidos
Materia
AGING
APOPTOSIS
CONNEXIN43
HMGB1
MIR21
OSTEOCYTE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/53391
Acceder
id CONICETDig_69ec88a9862501ececa663cc6650f41d
oai_identifier_str oai:ri.conicet.gov.ar:11336/53391
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with agingDavis, Hannah M.Pacheco Costa, RafaelAtkinson, Emily G.Brun, Lucas Ricardo MartínGortazar, Arancha R.Harris, JuliaHiasa, MasahiroBolarinwa, Surajudeen A.Yoneda, ToshiyukiIvan, MirceaBruzzaniti, AngelaBellido, TeresitaPlotkin, Lilian I.AGINGAPOPTOSISCONNEXIN43HMGB1MIR21OSTEOCYTEhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.Fil: Davis, Hannah M.. Indiana University; Estados UnidosFil: Pacheco Costa, Rafael. Indiana University; Estados UnidosFil: Atkinson, Emily G.. Indiana University; Estados UnidosFil: Brun, Lucas Ricardo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Indiana University; Estados UnidosFil: Gortazar, Arancha R.. Universidad San Pablo; EspañaFil: Harris, Julia. Indiana University; Estados UnidosFil: Hiasa, Masahiro. Indiana University; Estados UnidosFil: Bolarinwa, Surajudeen A.. Indiana University; Estados UnidosFil: Yoneda, Toshiyuki. Indiana University; Estados UnidosFil: Ivan, Mircea. Indiana University; Estados UnidosFil: Bruzzaniti, Angela. Indiana University; Estados UnidosFil: Bellido, Teresita. Indiana University; Estados UnidosFil: Plotkin, Lilian I.. Indiana University; Estados UnidosWiley Blackwell Publishing, Inc2017-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/53391Davis, Hannah M.; Pacheco Costa, Rafael; Atkinson, Emily G.; Brun, Lucas Ricardo Martín; Gortazar, Arancha R.; et al.; Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging; Wiley Blackwell Publishing, Inc; Aging Cell; 16; 3; 6-2017; 551-5631474-97181474-9726CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1111/acel.12586info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12586info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:25:05Zoai:ri.conicet.gov.ar:11336/53391instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:25:05.449CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
title Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
spellingShingle Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
Davis, Hannah M.
AGING
APOPTOSIS
CONNEXIN43
HMGB1
MIR21
OSTEOCYTE
title_short Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
title_full Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
title_fullStr Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
title_full_unstemmed Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
title_sort Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging
dc.creator.none.fl_str_mv Davis, Hannah M.
Pacheco Costa, Rafael
Atkinson, Emily G.
Brun, Lucas Ricardo Martín
Gortazar, Arancha R.
Harris, Julia
Hiasa, Masahiro
Bolarinwa, Surajudeen A.
Yoneda, Toshiyuki
Ivan, Mircea
Bruzzaniti, Angela
Bellido, Teresita
Plotkin, Lilian I.
author Davis, Hannah M.
author_facet Davis, Hannah M.
Pacheco Costa, Rafael
Atkinson, Emily G.
Brun, Lucas Ricardo Martín
Gortazar, Arancha R.
Harris, Julia
Hiasa, Masahiro
Bolarinwa, Surajudeen A.
Yoneda, Toshiyuki
Ivan, Mircea
Bruzzaniti, Angela
Bellido, Teresita
Plotkin, Lilian I.
author_role author
author2 Pacheco Costa, Rafael
Atkinson, Emily G.
Brun, Lucas Ricardo Martín
Gortazar, Arancha R.
Harris, Julia
Hiasa, Masahiro
Bolarinwa, Surajudeen A.
Yoneda, Toshiyuki
Ivan, Mircea
Bruzzaniti, Angela
Bellido, Teresita
Plotkin, Lilian I.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv AGING
APOPTOSIS
CONNEXIN43
HMGB1
MIR21
OSTEOCYTE
topic AGING
APOPTOSIS
CONNEXIN43
HMGB1
MIR21
OSTEOCYTE
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
Fil: Davis, Hannah M.. Indiana University; Estados Unidos
Fil: Pacheco Costa, Rafael. Indiana University; Estados Unidos
Fil: Atkinson, Emily G.. Indiana University; Estados Unidos
Fil: Brun, Lucas Ricardo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. Indiana University; Estados Unidos
Fil: Gortazar, Arancha R.. Universidad San Pablo; España
Fil: Harris, Julia. Indiana University; Estados Unidos
Fil: Hiasa, Masahiro. Indiana University; Estados Unidos
Fil: Bolarinwa, Surajudeen A.. Indiana University; Estados Unidos
Fil: Yoneda, Toshiyuki. Indiana University; Estados Unidos
Fil: Ivan, Mircea. Indiana University; Estados Unidos
Fil: Bruzzaniti, Angela. Indiana University; Estados Unidos
Fil: Bellido, Teresita. Indiana University; Estados Unidos
Fil: Plotkin, Lilian I.. Indiana University; Estados Unidos
description Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43-silenced MLO-Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase-3 activation and exhibit increased levels of apoptosis-related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro-survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43-expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis-related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high-mobility group box-1 (HMGB1)], and caspase-3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1-RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.
publishDate 2017
dc.date.none.fl_str_mv 2017-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/53391
Davis, Hannah M.; Pacheco Costa, Rafael; Atkinson, Emily G.; Brun, Lucas Ricardo Martín; Gortazar, Arancha R.; et al.; Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging; Wiley Blackwell Publishing, Inc; Aging Cell; 16; 3; 6-2017; 551-563
1474-9718
1474-9726
CONICET Digital
CONICET
url http://hdl.handle.net/11336/53391
identifier_str_mv Davis, Hannah M.; Pacheco Costa, Rafael; Atkinson, Emily G.; Brun, Lucas Ricardo Martín; Gortazar, Arancha R.; et al.; Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging; Wiley Blackwell Publishing, Inc; Aging Cell; 16; 3; 6-2017; 551-563
1474-9718
1474-9726
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1111/acel.12586
info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12586
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.891075

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